Integrative Regulation of Metabolism, Behavior, and Circadian Rhythms: Translational Insights from Obesity to CDKL5 Deficiency Disorder mouse models

This PhD thesis is organized into two research lines. The first part investigates the effects of intermittent fasting (IF) in a mouse model of diet-induced obesity. IF, combined with a balanced diet, improved metabolic and behavioral phenotypes in obese mice. Succinate emerged as a potential mediator of these benefits, and its supplementation mimicked the metabolic and behavioral effects of IF and reduced hippocampal inflammation. These findings suggest that succinate may represent a biochemical correlate of the metabolic, neuroinflammatory, and behavioral improvements induced by IF. The second part examines circadian rhythm alterations in CDKL5 deficiency disorder (CDD). We assessed behavioral, metabolic, and molecular circadian rhythms in a mouse model of CDD. CDKL5 KO mice showed altered locomotor activity and body temperature, especially around day-night transitions, along with shifts in food intake and respiratory exchange ratio. At the molecular level, transcriptomic profiling of the suprachiasmatic nucleus and hippocampus revealed a profound reorganization of the rhythmic transcriptome, with extensive redistribution of oscillatory gene expression. In addition, a microglial signature emerged as a potential output of the altered circadian profile. Overall, this work provides novel evidence for a role of circadian rhythms in CDD pathophysiology and highlights them as a potential therapeutic target.